Neuroendocrine cells (or endocrine-paracrine cells, or amine precursor uptake and decarboxylation cells) are intraepithelial cells with hybrid neuroendocrine and epithelial characteristics. These cells are widely distributed within the urethroprostatic region, with cells in the prostatic and penile urethra, prostatic ducts, and peripheral prostate. Prostate neuroendocrine cells are regulatory cells. Often, prostate neuroendocrine cells contain a biogenic amine, usually serotonin. In addition, prostate neuroendocrine cells contain one or more neuropeptides. These neuropeptides include chromogranin A (CgA), neuron specific enolase (NSE), substance P, calcitonin, somatostatin, neurotensin, bombesin, and even parathyroid hormone-related protein and thyroid-stimulating hormone-like peptide with chain homology. Some subpopulations of neuroendocrine cells also contain epidermal growth factor receptor and c-erbB-2. This type of prostate cell co-proliferates as a malignant epithelial component in most, if not all, prostatic carcinomas--which has been overlooked until very recently.
Normal neuroendocrine cells of the prostate do not contain androgen receptor and, therefore, are not regulated by androgen. As a result, neuroendocrine differentiation usually is associated with the increase of the NSE and CgA markers and rises with the increase of hormonal resistance in prostate cancer. Apparently, neuroendocrine cells in the prostate tumor gain growth advantage during hormonal deprivation therapy; they not only proliferate after androgen ablation therapy, but also have a tendency of becoming malignant. Consequently, prostatic tumors with extensive neuroendocrine differentiation were found to behave aggressively and are usually associated with a poor prognosis. Nearly all, if not all, prostatic carcinomas have some degree of neuroendocrine differentiation.
Pure neuroendocrine malignancies of the prostate also can be found in small cell carcinoma and carcinoid-like tumors. The malignancies in both cases, while rare, are highly aggressive and malignant. Understandably, it is critical that neuroendocrine differentiation in prostatic tumor be detected early. Patients with prostate cancer ideally should be evaluated for new treatment strategies before tumors become malignant. Chemotherapeutic regimens similar to those used in small cell carcinoma of the lung have been found to be beneficial for small cell carcinoma of the prostate.
Two markers expressed by tumor tissues, CgA and NSE, have been used to detect neuroendocrine differentiation. Positive immunostain for both markers in the tumor tissue biopsies correlates with poor prognosis and short survival intervals. Whether their serum or plasma concentrations are useful--as prognostic markers, however, is unclear. Serum markers are a more global indicator and a more objective quantifier of the neuroendocrine differentiation of tumors. The serum concentration of CgA, for example, reflects the activity of not only the primary tumor, but also its associated metastasis. Researchers have found both elevated plasma CgA and NSE for prostate cancers showing hormonal resistance. They found that determining neuroendocrine differentiation by NSE or CgA immunoassays was not helpful in the prediction of progressive localized prostatic carcinoma. Other researchers have found elevated plasma CgA in 48% of 25 patients with stage D2 prostate cancer. In another study, researchers did not find any of their patients with carcinoma of the prostate who had elevated serum values of NSE, despite the presence of NSE-positive tumor cells in 77% of the tumors. However, they not only found elevated serum values of CgA in 59% of their patients, but also a positive correlation between the number of CgA-staining cells and the serum values of CgA. Accordingly, CgA is a more useful serum marker in predicting the extent of neuroendocrine differentiation in prostatic tumors.
Neuroendocrine cells are not only present in prostate tumor. In one study, small proliferating nodules of benign prostate hyperplasia (BPH) contained abundant serotonin positive neuroendocrine cells and 10.7% of patients with BPH had abnormally high NSE levels. In fact, many of the D2 prostate cancer patients containing low tPSA (less than 4 ng/mL) had elevated CgA in the serum. Therefore, CgA may complement the tPSA assay in order to diagnose the presence of cancer. Interestingly, researchers have observed that even though there were elevated serum CgA levels in BPH patients, the plasma CgA levels in BPH patients usually fell below 100 ng/mL, whereas 50% of their cancer patients (D2) had levels of CgA greater than 100 ng/mL. CgA is also the major soluble protein in catecholamine-storage vesicles, which is stored and released by exocytosis with catecholamines and has been a useful index of sympathoadrenal catecholamine release in laboratory animals.
Continued progression of prostate cancer during endocrine therapy is a major clinical problem. Many studies suggest that prostatic cell lines may be stimulated to invade with neuropeptides secreted by neuroendocrine cells. Certain neuroendocrine peptides can increase the invasive potential of prostatic carcinoma cells and may thereby contribute to the rapid progression and aggressive clinical course of prostate tumors containing neuroendocrine elements.
From the foregoing, it will be appreciated that it would be an advancement in the art to provide a method for detecting resistance during the hormonal treatment of prostate cancer to prevent further development of malignant tumors.
It would be a further advancement in the art if the method provided earlier detection of hormonal resistance in prostate cancer patients than currently available tPSA assays.
Finally, it would be another advancement in the art if the method differentiated between prostate cancer and BPH.
Such a method is disclosed and claimed herein.